Learning and

Memory

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Learning and Memory

“Our memory makes us who

we are, and it is one of the
most intimate parts of
ourselves”

By G. Radvansky 2
Learning and Memory

Definitions
Memory

 The location where information is kept

Refer to the thing that holds the content of experience,

as in a memory trace or engram

 The mental process used to acquire, store or retrieve

information of all sorts

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Learning and Memory

Definitions
Learning

 Any change in the potential of people to alter their

behavior as a consequence of experience

The acquisition of associations, often in the context of

studies of conditioning

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 Learning and Memory

Brenda Milner, Montreal Neurological Institute Eric Kandel, Columbia University

McGill university

Brenda Milner

Columbia university (Nobel prize physiology or

medicine 2000) 5
Learning and Memory

Lecture outline:
- Different types of memory, a story about H.M.
- Cellular mechanism of implicit memory: Aplysia
- Cellular and molecular mechanism of explicit memory, the hippocampus and
the prefrontal cortex

Henry Molaison

Photo credit: Courtesy Suzanne Corkin

http://www.molluscs.at/6
Learning and Memory

Implicit and explicit memory

The story of H.M (1926-2008)

At 9y old, he was hit and knock-out by someone riding a bicycle.

Brain damage.
Few years after the shock, he started to suffer of untreatable bilateral temporal lobe
seizure (epilepsy).

At 27y old, he received a surgery from the neurosurgeon William Scoville.

At surgery: The hippocampus, the amygdala and part of the temporal cortex were
removed bilaterally.

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Learning and Memory

H.M
The surgery

Effect of the surgery:

• Seizure are under control
• Devastating memory deficit

• Normal short term memory (sec or min)

• Perfectly good memory of long-term events
that occurred before the surgery
• Remember his name, his job, childhood
events
• Few deficit about event from the last year
(minor retrograde amnesia)
• Good language
• Same IQ than before the surgery.

• So what is wrong with H.M ? 8

Figure65-2 Kandel et al. Principle of neural science 5 edition
th
Learning and Memory
H.M
Motor skill ?

Perfectly normal, can learn and remember motor activity

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Learning and Memory
H.M

Henry loved to relate the few clear memories of his childhood, over and over, […] Corkin
heard those stories many times over the years; every time she left the room for a minute and
returned to Henry he introduced himself as if they had never met before, and told the stories
again.
The guardian

No more ability to transfer short-term memory into

long-term memory
and spatial orientation deficit

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 Learning and Memory

The various form of memory

Unconscious conscious

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Kandel et al. Principle of neural science 5 th edition
Learning and Memory

Cell biology of implicit memory system: Sensitization in Aplysia

The marine snail, Aplysia

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Learning and Memory

Why Aplysia ?

• Simple reflex behaviors that can be modified by different forms of learning

• Around 20000 neurons and less than 100 involved in the reflex pattern studied by
Kandel
• Some neurons are 1000um in diameter! Easy for cell recording, electrophysiology,
biochemical analysis
• Cells are easy to identify, can record the same cell in different individuals or image
the same cell in later recording session

The behaviour

The gill-withdrawal reflex

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Learning and Memory

The gill-withdrawal reflex = Defensive reflex

Sensitization:
enhancement of a
behavioral response to a
stimulus after application
of a different, noxious,
stimulus

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 Learning and Memory

Molecular biology of
short-term sensitization

The signalling pathway:

Serotonin5-HT receptor
(GPCR)activate adenylyl
cyclasecAMPPKA
phosphorylation of K+ channel
effect of AP on Calcium influx is
prolongedvesicle exocytosis
transmitter releaseactivation of
motoneuron

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Kandel et al. Principle of neural science 5 th edition
 Learning and Memory

Molecular biology of
short-term sensitization

PLCDAGPKC pathway

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 Learning and Memory

Molecular biology of
long-term sensitization

The signalling pathway:

Serotonin5-HT receptor
(GPCR)activate adenylyl
cyclasecAMPPKAMAPK
CREB-1 is activated immediate
early genes Ubiquitine
hydrolaseactivate proteasome
cleave a PKA regulatory subunit
(inhibitor)Persistent PKA
(~12h) phosphorylation of K+
channel effect of AP on Calcium
influx is prolongedvesicle
exocytosis transmitter
releaseactivation of motoneuron
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Kandel et al. Principle of neural science 5 th edition
Learning and Memory

Molecular biology of long-term sensitization

Stabilization of long term

facilitation process:

Growth of new synaptic connection

CREB-1 C/EBP (Enhancer Binding
Protein) CCAAT Genes involved
in growth of synapses

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Learning and Memory

Long-term memory is accompanied by :

- Larger number, size and vesicle complement at the active zones of
the presynaptic varicosities of sensory neurons

- increase number of presynaptic varicosities per sensory neurons

after long term sensitization

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Learning and Memory
The cell biology of an explicit memory system

Explicit memory: the conscious recall of information about

people, place, object. Also called declarative memory.
Two structures are critical for encoding and storing explicit
memory:
• The prefontal cortex (PFC)
• The hippocampus

PFC mediates working memory, information stored can be maintained for a very
short period of time and then rapidly forgotten exp: telephone number or can be
stored elsewhere as long-term memory

The hippocampus stores some stable declarative memory for days, years and some
for lifetime.

The ultimate storage is thought to be in the cerebral cortex.

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Learning and Memory

Anatomy of the hippocampus

• Very regular cellular organization and

connectivity.
• 3 principal neural pathways:
- Perforant Path
- mossy fiber pathway
- Schaffer collateral pathway

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Learning and Memory

The trisynaptic circuitry

Perforant pathway: From the entorhinal cortex, form excitatory connections with granule
cell of the dentate gyrus.
Mossy fiber pathway: Form by the axons of the granule cells of the DG that make synaptic
contact with the pyramidal cells of CA3.
Schaffer collateral pathway: Connect pyramidal cell from the CA3 with the pyramidal cells of
the CA1.
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Learning and Memory

Explicit memory in mammals involves long-term potentiation (LTP) in the hippocampus

A brief high-frequency train of stimuli to any of the three synaptic pathway increases
the amplitude of the EPSP in the target hippocampal neuron.
Can be examined in the intact animal (days or week) or in brain slices (hours).

Early vs Late LTP;

single vs multiple
stimulus

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Learning and Memory

Molecular biology of LTP

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Learning and Memory

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Learning and Memory

Model for early and late LTP

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Learning and Memory

New neurons for new memories

Adult neurogenesis in the hippocampus and memory formation

Experiment:

Enriched environment
and more animals

Enhances memory functions

Is it correlate with neurogenesis ?
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Learning and Memory
Use of 5-bromo-2’-deoxyuridine (BrdU) to label new born cell in the dentate gyrus.
BrdU is incorporated into replicating DNA during the S phase of mitosis.
Immunohistochemistry to detect it.

Survival rate of
newborn cells increase
under enriched
environment  more
cells.

The running activity plays an

important role in this effect.
(sport is good for memory!)

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Learning and Memory
If synaptic connections could only be enhanced and never attenuated  Saturation !
But individual are able to learn and store new memories throughout a lifetime
Mechanism to downregulate synaptic function ?

Long Term Depression (LTD)

Internalization
of AMPA
receptor

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Learning and Memory

Behavior associated with LTD?

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What was important
in the lecture ?

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